7-thiaprostaglandins E, and process for producing same

ABSTRACT

7-thiaprostaglandins E 1  which are compounds represented by the following formula [I] or their enantiomers or mixtures thereof in any ratio: ##STR1## where R 1  represents a hydrogen atom, a C 1  -C 10  alkyl group, a C 2  -C 20  alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C 3  -C 10  cycloalkyl group, a substituted or unsubstituted phenyl (C 1  -C 2 ) alkyl group, or one equivalent cation; R 2  and R 3 , which may be the same or different, represent a hydrogen atom, a tri (C 1  -C 7 ) hydrocarbon silyl group, or a group forming an acetal linkage together with an oxygen atom of a hydroxyl group; R 4  represents a hydrogen atom, a methyl group or a vinyl group; R 5  represents a linear or branched C 3  -C 8  alkyl group, a linear or branched C 3  -C 8  alkenyl group, a linear or branched C 2  -C 8  alkynyl group, a phenyl group which may be substituted, a phenoxy group which may be substituted, a C 3  -C 10  cycloalkyl group which may be substituted, or a linear or branched C 1  -C 5   alkyl group which may be substituted with a C 1  -C 6  alkoxy group, a phenyl group which may be substituted, a phenoxy group which may be substituted or a C 3  -C 10  cycloalkyl group which may be substituted; X represents an ethylene group, a vinylene group or an ethylene group; n represents 0 or 1; the expression represents an ethylene group or a vinylene group, provided that when n is o and x is an ethylene group, R 5  is not a linear or branched C 3  -C 8  alkyl group or a C 3  -C 10  cycloalkyl group which may be substituted. 
     Such compounds are especially useful for the treatment and prevention of digestive organ diseases such as a duodenal ulcer or a gastric ulcer.

This application is a continuation of application Ser. No. 07/120,726,filed Nov. 13, 1990 which is a continuation of Ser. No. 796,571 filedOct. 25, 1985.

DESCRIPTION

1. Technical Field

The present invention relates to novel 7-thiaprostaglandins E₁ and aprocess for producing the same. More specifically, the present inventionrelates to novel 7-thiaprostaglandians E₁ useful as medicines and aprocess for producing said 7-thiaprostaglandins E₁ which comprisesreacting an organolithium compound with a copper compound, then reactingthe resultant reaction product with 2-organothio-2-cyclopentenones, andoptionally subjecting the resultant product to deprotection, hydrolysis,salt-formation and/or reduction reaction.

2. Background of the Art

Natural prostaglandins are known as local hormones having a biologicallyand pharmacologically high activity and therefore a large number ofstudies on their derivatives have been made. Among naturalprostaglandins, prostanglandin E₁ has strong blood platelet aggregationinhibition effect and vasodilatation effect, etc. and begins to be usedfor clinical applications.

The greatest defect of natural prostaglandins, especially prostaglandinsE₁, is that they can not be orally administered because they are rapidlymetabolized when orally administered and therefore they must be usuallyadministered by an intravenous injection.

Conventionally, synthetic prostaglandins prepared by replacing one ortwo carbon atoms forming the skeleton of natural prostaglandins with asulfur atom have been variously studied.

For example, there are known 1-thiaprostaglandin E₂ or F₂α wherein thecarbon atom at the 1-position of natural prostaglandins is replaced witha sulfur atom (J. Org. Chem., 40, 521, (1975)),3-thia-11-deoxyprostaglandin E₁ (Tetrahedron Letters, 1975, 765; and J.Med. Chem., 20, 1662 (1977)), 7-thiaprostaglandins F.sub.α (J. Amer.Chem. Soc., 96, 6757 (1974)), 9S-prostaglandins E₁ (Tetrahedron Letters,1974, 4267 and 4459; Tetrahedron Letters, 1976, 4793; and Heterocycles,6, 1097 (1977)), 11-thiaprostaglandins E₁ or F₁α (Tetrahedron Letters,1975, 1165), 13-thiaprostaglandins E or F (U.S. Pat. No. 4,080,458(1978)), and 15-thiaprostaglandins E₂ (Tetrahedron Letters, 1977, 1629).

Moreover, there are known 11-deoxy-7-thiaprostaglandins E₁ (U.S. Pat.No. 4,180,672), natural type 7-thiaprostaglandins E₁ containing ahydroxyl group at the 15-position (U.S. Pat. No. 4,466,980) ornon-natural type 15-deoxy-16-hydroxy-3-thiaprostaglandins E₁ containinga hydroxyl group at the 16-position (Japanese Unexamined PatentPublication No. 54-22342).

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide novel non-natural type15-deoxy-16-hydroxy-7-thiaprostaglandins E₁ containing a hydroxyl groupat the 16-position.

Another object of the present invention is to provide novel natural type7-thiaprottaglandins E₁ containing an unsaturated bond at the 4-positionor a specific substituent such as an alkenyl group or an alkynyl groupat the 15-position.

A further object of the present invention is to provide novel7-thiaprostaglandins E₁ which are especially useful for the treatment orprevention of digestive organ diseases such as a duodenal ulcer and agastric ulcer.

A still another object of the present invention is to provide novel7-thiaprostaglandins E₁ which can be orally administered.

A further object of the present invention is to provide a process forproducing novel 7-thiaprostaglandins E₁ which is excellent forindustrial purposes.

Other objects and advantages of the present invention will be apparentfrom the following descriptions.

The above-mentioned objects and advantages of the present invention areattained by the following 7-thiaprostaglandins E₁.

That is, the present invention is 7-thiaprostaglandins E₁ which arecompounds represented by the following formula [I] or their enantiomersor mixtures thereof in any ratio: ##STR2## wherein R¹ represents ahydrogen atom, a C₁ -C₁₀ alkyl group, a C₂ -C₂₀ alkenyl group, asubstituted or unsubstituted phenyl group, a substituted orunsubstituted C₃ -C₁₀ cycloalkyl group, a substituted or unsubstitutedphenyl (C₁ -C₂) alkyl group, or one equivalent cation; R² and R³, whichmay be the same or different, represent a hydrogen atom, a tri (C₁ -C₇)hydrocarbon silyl group, or a group forming an acetal linkage togetherwith an oxygen atom of a hydroxyl group; R⁴ represents a hydrogen atom,a methyl group, or a vinyl group; R⁵ represents a linear or branched C₃-C₈ alkyl group, a linear or branched C₃ -C₈ alkenyl group, a linear orbranched C₃ -C₈ alkynyl group, a phenyl group which may be substituted,a phenoxy group which may be substituted, a C₃ -C₁₀ cycloalkyl groupwhich may be substituted, or a linear or branched C₁ -C₅ alkyl groupwhich is substituted with a C₁ -C₆ alkoxy group, a phenyl group whichmay be substituted, a phenoxy group which may be substituted, or a C₃-C₁₀ cycloalkyl group which may be substituted; X represents an ethylenegroup, a vinylene group or an ethynylene group; n represents 0 or 1, theexpression represents an ethylene group or a vinylene group; providedthat when n is 0 and X is an ethylene group, R⁵ is not a linear orbranched C₃ -C₈ alkyl group or a C₃ -C₁₀ cycloalkyl group which may besubstituted.

BEST MODE OF CARRYING OUT THE INVENTION

In the formula [I], R¹ represents a hydrogen atom, a C₁ -C₁₀ alkylgroup, a C₂ -C₂₀ alkenyl group, a substituted or unsubstituted phenylgroup, a substituted or unsubstituted C₃ -C₁₀ cycloalkyl group, asubstituted or unsubstituted phenyl (C₁ -C₂) alkyl group, or oneequivalent cation.

The C₁ -C₁₀ alkyl groups may be linear on branched and may include, forexample, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The C₂ -C₂₀ alkenyl groups may include, for example, allyl, isoprenyl,geranyl, citronellyl, and retinyl.

The substituent of the substituted or unsubstituted phenyl ispreferably, for example, a halogen atom, a hydroxy group, a C₂ -C₇acyloxy group, a C₁ -C₄ alkyl group which may be substituted with ahalogen atom, a C₁ -C₄ alkoxy group which may be substituted with ahalogen atom, a nitrile group, a carboxyl group or a (C₁ -C₆)alkoxycarbonyl group. The halogen atom is, for example, fluorine,chlorine or bromine and particularly preferably fluorine or chlorine.The C₂ -C₇ acyloxy group may include, for example, acetoxy,propionyloxy, n-butyryloxy, iso-butyryloxy, n-valeryloxy iso-valeryloxy,caproyloxy, enanthyloxy or benzoyloxy.

The C₁ -C₄ alkyl groups which may be substituted with a halogen atom maypreferably include, for example, methyl, ethyl, n-propyl, iso-propyl,n-butyl, chloromethyl, dichloromethyl, and trifluoromethyl. The C₁ -C₄alkoxy groups which may be substituted with a halogen atom maypreferably include, for example, methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, chloromethoxy, dichloromethoxy andtrifluoromethoxy. The (C₁ -C₆) alkoxycarbonyl groups may include, forexample, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl andhexyloxycarbonyl.

The substituted phenyl group may have 1 to 3, preferably one,substituents as mentioned above.

The substituted or unsubstituted C₃ -C₁₀ cycloalkyl groups may besubstituted with a similar substituent as mentioned above or may be anunsubstituted cycloalkyl group, such as cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

The substituted or unsubstituted phenyl (C₁ -C₂) alkyl groups may besubstituted with a similar substituent as mentioned above or mayinclude, for example, unsubstituted benzyl, α-phenethyl and β-phenethyl.

The equivalent cations may include, for example, ammonium cations suchas tetramethylammonium, monomethylammonium, dimethylammonium,trimethylammonium, benzylammonium, phenethylammonium, morpholiniumcation, monoethanolammonium and piperidinium cation; alkali metalcations such as Na⁺ and K⁺ ; and divalent or trivalent metal cationssuch as 1/2 Ca²⁺, 1/2 Mg²⁺, 1/2 Zn²⁺ and 1/3 Al³⁺.

R¹ is preferably a hydrogen atom, a C₁ -C₁₀ alkyl group, a C₂ -C₂₀alkenyl group or one equivalent cation.

In the formula [I], R² and R³ may be the same or different and representa hydrogen atom, a tri(C₁ -C₇) hydrocarbon silyl group or a groupforming an acetal linkage together with an oxygen atom of a hydroxylgroup.

The tri (C₁ -C₇) hydrocarbon silyl group may preferably include, forexample, a tri (C₁ -C₄) alkylsilyl such as trimethylsilyl,triethylsilyl, and t-butyldimethylsilyl; a diphenyl (C₁ -C₄) alkylsilylsuch as t-butyldiphenylsilyl or tribenzylsilyl.

The group forming an acetal linkage together with an oxygen atom of ahydroxyl group may include, for example, methoxyethyl, 1-ethoxyethyl,2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy) methyl,benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexa-4-yl. Of these,2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl,2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy) methyl or6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexa-4-yl is especiallypreferable.

As R² or R³, among the above-mentioned groups, a hydrogen atom, a tri (C) alkylsilyl group, a diphenyl (C₁ -C₄) alkylsilyl group, a2-tetrahydropyranyl group, a 2- group, an 1-ethoxyethyl group, a2-methoxy-2-propyl group, a 2-ethoxy-2-propyl group, a (2-methoxyethoxy)methyl group or a 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexa-4-ylgroup is preferable.

In the formula [I], R⁴ represents a hydrogen atom, a methyl group or avinyl group.

In the formula [I], R⁵ represents a linear or branched C₃ -C₈ alkylgroup, a linear or branched C₃ -C₈ alkenyl group, a linear or branchedC₃ -C₈ alkynyl group, a phenyl group which may be substituted, a phenoxygroup which may be substituted, a C₃ -C₁₀ cycloalkyl group which may besubstituted, or a linear or branched C₁ -C₅ alkyl group which may besubstituted with a C₁ -C₆ alkoxy group, a phenyl group which may besubstituted, a phenoxy group which may be substituted or a C₃ -C₁₀cycloalkyl group which may be substituted.

The linear or branched C₃ -C₈ alkyl groups may include, for example,n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,1-methyl-1-butyl, 2-methylhexyl, 2-methyl-2-hexyl, 2-hexyl,1,1-dimethylpentyl, preferably butyl, pentyl, hexyl, (2R)- or(2S)-2-methylhexyl, 2-hexyl, 1-methyl-1-butyl, 2-methyl-1-butyl, morepreferably butyl. A hydrogen atom to be attached to such alkyl groupsmay be deuterium and tritium.

The linear or branched C₃ -C₈ alkenyl groups may include, for example,1-butenyl, 2-butenyl, 1-pentenyl, and 2-methyl-4-hexenyl. A hydrogenatom to be attached to such alkenyl groups may be deuterium and tritium.

The linear or branched C₃ -C₈ alkynyl groups may include, for example,1-butynyl, 2-butynyl, 1-pentynyl, and 2-methyl-4-hexynyl.

The substituent of a phenyl group which may be substituted and a phenoxygroup which may be substituted may be a similar substituent as mentionedfor the substituent of a substituted phenyl group of R¹ the substituentof a C₃ -C₇ cycloalkyl group may be a similar substituent as mentionedfor the substituent of a substituted phenyl group of R¹. Theunsubstituted C₃ -C₇ cycloalkyl group may include, for example,cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl andcyclodecyl.

The C₁ -C₆ alkoxy groups in the linear or branched C₁ -C₅ alkyl groupwhich may be substituted with a C₁ -C₆ alkoxy group, a phenyl groupwhich may be substituted, a phenoxy group which may be substituted or aC₃ -C₁₀ cycloalkyl group which may be substituted may include, forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, andhexyloxy. The phenyl group which may be substituted and the phenoxygroup which may be substituted may preferably include those mentionedabove. The C₃ -C₁₀ cycloalkyl groups which may be substituted maypreferably include those mentioned above. The linear or branched C₁ -C₅alkyl groups may-include, for example, methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and pentyl. Thesubstituent may be attached to the alkyl group at any position.

As R⁵, butyl, pentyl, 1-methyl-1-butyl, 2-methyl-1-butyl, cyclopentyl,cyclohexyl and phenyl are preferable.

In the formula [I], X represents an ethylene group, a vinylene group oran ethynylene group. The vinylene group may be a cis-vinylene group, atrans-vinylene group or mixtures thereof in any ratio.

A hydrogen atom to be attached to such an ethylene group or a vinylenegroup may be deutrium and tritium. The expression represents an ethylenegroup or a vinylene group. The vinylene group may be a cis-vinylenegroup, a trans-vinylene group or mixtures thereof in any ratio.

In the formula [I], n represents 0 or 1.

In the formula [I], when n is 0 and X represents an ethylene group, R⁵is not a linear or branched C₃ -C₈ alkyl group or a C₃ -C₁₀ cycloalkylgroup which may be substituted.

The 7-thiaprostaglandins E₁ of the present invention are classified intothe following two classes on the basis of the above-mentioned definitionof n, X and R⁵.

(i) 7-thiaprostaglandins E₁ in the case of n=1

In the case of n=1, the 7-thiaprostaglandins E₁ of the present inventionare represented by the following formula [I-1]: ##STR3## wherein R¹, R²,R³, R⁴, R⁵, X and the expression are the same as defined above. In thecase, the 7-thiaprostaglandins E₁ are15-deoxy-16-hydroxy-7-thiaprostaglandins E₁.

(ii) 7-thiaprostaglandins E₁ in the case of n=0

In the case of n=0, the 7-thiaprostaglandins E₁ of the present inventionare represented by the following formula [I-2]: ##STR4## wherein R¹, R²,R³, R⁴, R⁵, X and the expression are the same as defined above, providedthat when X is an ethylene group, R⁵ is not a linear or branched C₃ -C₈alkyl group or a C₃ -C₁₀ cycloalkyl group which may be substituted. Inthis case, the 7-thiaprostaglandins E₁ contain an unsaturated bond atthe 4-position or a substituent such as an alkynyl group or an alkenylgroup at the 15-position.

In the compound of the formula [I], the configuration of a substituentattached on the cyclopentanone ring is the same as has naturalprostaglandin E₁. Therefore, such a stereoisomer is especially useful.The present invention includes stereoisomers which are the enantiomer ofthe above-mentioned stereoisomer and have the following formula [I] ent,or mixtures thereof in any ratio ##STR5## wherein R¹, R², R³, R⁴, R⁵, n,X and the expression the same as defined above. Since the carbon atom towhich OR³, R⁴ and R⁵ are attached by substitution is an asymmetriccarbon atom, two types of optical isomers exist. The present inventionincludes any of these optical isomers or mixtures thereof in any ratio.

Preferable examples of the novel 7-thiaprostaglandins E₁ of the formula[I] which are provided by the present invention may include thefollowing compounds.

(01) 15-deoxy-16-hydroxy-7-thiaprostaglandin E₁

(02) 15-deoxy-16-hydroxy-18-oxa-7-thiaprostaglandin E₁

(03) 18,19,20-trinor-15-deoxy-16-hydroxy-17-phenoxy-7-thiaprostaglandinE₁

(04) 15-deoxy-16-hydroxy-20-methyl-7-thiaprostaglandin E₁

(05) 15-deoxy-16-hydroxy-17,20-dimethyl-7-thiaprostaglandin E₁

(06)17,18,19,20-tetranor-15-deoxy-16-hydroxy-16-cyclopentyl-7-thiaprostaglandinE₁

(07)17,18,19,20-tetranor-15-deoxy-16-hydroxy-16-cyclohexyl-7-thiaprostaglandinE₁

(08) 15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁

(09) 15-deoxy-16-hydroxy-16-methyl-18-oxa-7thiaprostaglandin E₁

(10)18,19,20-trinor-15-deoxy-16-hydroxy-17-phenoxy-16-methyl-7-thiaprostaglandinE₁

(11) 15-deoxy-16-hydroxy-16,20-dimethyl-7thiaprostaglandin E₁

(12) 15-deoxy-16-hydroxy-16,17,20-trimethyl-7thiaprostaglandin E₁

(13)17,18,19,20-tetranor-15-deoxy-16-hydroxy-16-cyclopentyl-16-methyl-7-thiaprostaglandinE₁

(14)17,18,19,20-tetranor-15-deoxy-16-hydroxy-16-cyclohexyl-16-methyl-7-thiaprostaglandinE₁

(15) 15-deoxy-16-hydroxy-16-vinyl-7-thiaprostaglandin E₁

(16) 15-deoxy-16-hydroxy-16-vinyl-18-oxa-7-thiaprostaglandin E₁

(17)18,19,20-trinor-15-deoxy-16-hydroxy-17-phenoxy-16-vinyl-7-thiaprostaglandinE₁

(18) 15-deoxy-16-hydroxy-20-methyl-16-vinyl-7-thiaprostaglandin E₁

(19) 15-deoxy-16-hydroxy-17,20-dimethyl-16-vinyl-7-thiaprostaglandin E₁

(20)17,18,19,20-tetranor-15-deoxy-16-hydroxy-16-cyclopentyl-16-vinyl-7-thiaprostaglandinE₁

(21)17,18,19,20-tetranor-15-deoxy-16-hydroxy-16-cyclohexyl-16-vinyl-7-thiaprostaglandinE₁

(22) 15-deoxy-2,3-dehydro-16-hydroxy-7-thiaprostaglanding E₁

(23) 15-deoxy-2,3-dehydro-16-hydroxy-16-methyl-7-thiaprostaglandin E₁

(24) 15-deoxy-2,3-dehydro-16-hydroxy-16-vinyl-7-thiaprostaglandin E₁

(25) 4,4,5,5-dehydro-7-thiaprostaglandin E₁

(26) 4,4,5,5-dehydro-17-methyl-7-thiaprostaglandin E₁

(27) 4,4,5,5-dehydro-17,20-dimethyl-7-thiaprostaglandin E₁

(28) 4,4,5,5-dehydro-17(S),20-dimethyl-7-thiaprostaglandin E₁

(29) 4,4,5,5-dehydro-17(R),20-dimethyl-7-thiaprostaglandin E₁

(30)4,4,5,5-dehydro-16,17,18,19,20-pentanor-15-cyclohexyl-7-thiaprostaglandinE₁

(31)4,4,5,5-dehydro-16,17,18,19,20-pentanor-15-cyclopentyl-7-thiaprostaglandinE₁

(32) 4,4,5,5-dehydro-18-oxa-7-thiaprostaglandin E₁

(33)4,4,5,5-dehydro-17,18,19,20-tetranor-16-cyclohexyl-7-thiaprostaglandinE₁

(34) (4E)-4,5-dehydro-7-thiaprostaglandin E₁

(35) (4E)-4,5-dehyro-17(R),20-dimethyl-7-thiaprostaglandin E₁

(36) (4Z)-4,5-dehydro-7-thiaprostaglandin E₁

(37) (4Z)-4,5-dehydro-17(R),20-dimethyl-7-5 thiaprostaglandin E₁

(38) 17,17,18,18-dehydro-7-thiaprostaglandin E₁

(39) 17,17,18,18-dehydro-16-methyl-7-thiaprostaglandin E₁

(40) 18,18,19,19-dehydro-17-methyl-7-thiaprostaglandin E₁

(41) 18,18,19,19-dehydro-17,20-dimethyl-7-thiaprostaglandin E₁

(42) 19,20-dehydro-17,20-dimethyl-7-thiaprostaglandin E₁

(43) 19,20-dehydro-7-thiaprostaglandin E₁

(44) 17,18-dehydro-7-thiaprostaglandin E₁

(45) The 17,18-deuterated derivative of the compound (38)

(46) The 17,18-tritiated derivative of the compound (39)

(47) The 18,19-tritiated derivative of the compound (41)

(48) The methyl esters of the compounds (1) to (47)

(49) The ethyl esters of the compounds (1) to (47)

(50) The sodium salt of the compounds (1) to (47)

The 7-prostaglandins E₁ of the present invention which are compounds ofthe formula [I] or their enantiomers or mixtures thereof in any ratioare prepared by reacting an organolithium compound of the formula [II]##STR6## wherein R³¹ represents a tri(C₁ -C₇) hydrocarbon silyl group ora group forming an acetal linkage together with an oxygen atom of ahydroxyl group, and R⁴, R⁵ and n are the same as defined above, with acopper compound of the formula [III]:

    CuQ

wherein Q represents a halogen atom, a cyano group, a phenylthio groupor a 1-pentyl group, by then reacting the resultant reaction productwith 2-organothio-2-cyclopentenones of the following formula [IV] ortheir enantiomers or mixtures thereof in any ratio: ##STR7## wherein R¹¹represents a C₁ -C₁₀ alkyl group, a C₂ -C₂₀ alkenyl group, a substitutedor unsubstituted phenyl group, a substituted or unsubstituted C₃ -C₁₀cycloalkyl group, or a substituted or unsubstituted phenyl (C₁ -C₂)alkyl group; R²¹ represents a tri(C₁ -C₇) hydrocarbon silyl group or agroup forming an acetal linkage together with an oxygen atom of ahydroxyl group; and X and the expression are the same as defined above,and by optionally subjecting the resultant product to deprotection,hydrolysis, salt-formation and/or reduction reaction.

R³¹ in the organolithium compound of the formula [II] is defined as R³from which a hydrogen atom is removed. Such an organolithium compoundcan be prepared by a method known per se (J. Am. Chem. Soc., 94, 7210(1972); U.S. Pat. Nos. 4,180,672; and 4,466,930; and Japanese UnexaminedPatent Publication No. 4,466,930; and Japanese Unexamined PatentPublication (Kokai) No. 53-108929).

Q in the copper compound of the formula [III] represents a halogen atomsuch as chlorine, fluorine, and bromine, a cyano group, a phenylthiogroup or a 1-pentyl group. Such a copper compound is a known compound.

R²¹ in the 2-organothio-2-cyclopentenones of the formula [IV] is definedR² from which a hydrogen atom is removed. R¹¹ is defined as R¹ fromwhich a hydrogen atom and one equivalent cation are removed.

2-organothio-2-cyclopentenones of the formula [IV]in which theexpression is an ethylene group can be prepared by the followingsynthetic route: ##STR8##

With regard to these synthetic processes, reference will be made to U.S.Pat. Nos. 4,180,672; 4,466,980, etc.

2-Organothio-2-cyclopentenones of the formula [IV]in which theexpression is a vinylene group can be prepared by the followingsynthetic route: ##STR9##

With regard to these synthetic processes, reference will be made to U.S.Pat. No. 4,466,980.

In the present invention, the organolithium compound of the formula [II]is first reacted with the copper compound of the formula [III]. Thereaction is carried out in the presence of an organic medium. An inertnon-protonic organic medium which is liquid under the reactiontemperature and does not react with the reaction reagents is preferablyused.

Such inert non-protonic organic media may include, for example,saturated hydrocarbons such as pentane, hexane, heptane, andcyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene;ether solvents such as diethyl ether, tetrahydrofuran, dioxane,dimethoxyethane, and diethylene glycol dimethyl ether; and othernon-protonic polar solvents such as hexamethylphosphorictriamide (HMP),N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAA), dimethylsulfoxide, sulforan, and N-methylpyrrolidone. These solvents may be usedin the form of a mixture of two or more thereof.

The copper compound of the formula [III] is usually used in an amount of0.8 to 2.0 times by mole, preferably 1 to 1.2 times by mole, based onthe organolithium compound of the formula [II].

The reaction temperature is in the range of from -100° C. to 0° C., morepreferably from approximately -78° C. to -20° C. The reaction time isvariable depending on the reaction temperature. Usually, an about onehour reaction time at a temperature of -78° C. to -40° C. is sufficient.

The reaction is preferably carried out in an atmosphere of nitrogen orargon gas.

The thus-obtained reaction product is estimated to have the partialstructure represented by the following formula: ##STR10## (TetrahedronLett., 21, 1247 (1980)).

Then, the above-mentioned reaction product is reacted with the2-organothio-2-cyclopentenones of the formula [IV]. This reaction ispreferably carried out by adding the organothio-2-cyclopentenones to thesame reaction system without isolating the reaction product after thereaction of the organolithium compound of the formula [II] and thecopper compound of the formula [III].

The 2-organothio-2-cyclopentenones are usually used in an amount of 0.5to 1.5 times by mole, preferably 0.7 to 1.2 times by mole, based on theorganolithium compound of the formula [II].

The reaction temperature is in the range of from -120° C. to 0° C.,preferably from -90° C. to -30° C. Although the reaction time isvariable depending upon the reaction temperature, it is usually 10minutes to 2 hours.

The reaction is carried out in an atmosphere of nitrogen or argon gas.

In the practice of the reaction, when a trivalent phosphorus compound,e.g., trialkylphosphines (e.g., triethylphosphine, tributylphosphine),trialkyl phosphites (e.g., trimethyl phosphite, triethyl phosphite,triisopropyl phosphite, tri-n-butyl phosphite),hexamethylphosphorustriamide or triphenylphosphine is used, the reactionsmoothly proceeds. Especially tributylphosphine andhexamethylphosphorustriamide are preferably used.

Such trivalent organic phosphorus compounds may be added during thereaction of the organolithium compound of the formula [II] and thecopper compound of the formula [III].

Thus, there are obtained compounds of the formula [I] in which thehydroxyl group is protected and the carboxylic acid at the 1-position isin the form of an ester. Since the production process of the presentinvention uses a reaction which proceeds stereospecifically, from thestarting material having the configuration represented by the formula[IV], a compound having the configuration represented by the formula[I], is obtained, and from the enantiomer of the formula [IV], anenantiomer of the formula [I] represented by the formula [I]ent isobtained.

At the completion of the reaction, the resultant product is separatedfrom the reaction mixture and purified in a conventional manner. Forexample, extraction, washing, chromatography or combinations thereof maybe used.

Moreover, the compounds as obtained herein wherein the hydroxyl group isprotected and the carboxylic acid at the 1-position is in the form of anester is then optionally subjected to deprotection, hydrolysis orsalt-formation reaction.

Alternatively, the compounds may be subjected to a reduction reaction inwhich X in the formula [I] which is an ethynylene group or a vinylenegroup is reduced, or to a reduction reaction in which R⁵ in the formula[I] which is a linear or branched C₃ -C₈ alkenyl group, or a linear orbranched C₃ -C₈ alkynyl group is reduced.

The removal of the protective group (R²¹ and R³¹) of a hydroxyl group,when the protective group is a group forming an acetal linkage togetherwith an oxygen atom of a hydroxyl group, is conveniently carried out ina reaction solvent such as water, tetrahydrofuran, ethyl ether, dioxane,acetone, and acetonitrile, in the presence of a catalyst such as aceticacid, the pyridinium p-toluensulfonate or a cation exchange resin. Thereaction is usually carried out at a temperature ranging from -78° C. to+50° C. for approximately 10 minutes to 3 days. In the case where theprotective group is a tri (C₁ -C₇) hydrocarbon silyl group, the reactionis carried out in the above-mentioned reaction solvents in the presenceof a catalyst such as acetic acid, tetrabutylammonium fluoride, cesiumfluoride, hydrofluoric acid and hydrogen fluoride-pyridine at the sametemperature for the same period.

The removal of the protective group (R¹¹) of a carboxy group, i.e.,hydrolysis reaction, is carried out in water or a solvent containingwater in the presence of an enzyme such as lipase and esterase at atemperature ranging from -10° C. to +60° C. for approximately 10 minutesto 24 hours.

In accordance with the present invention, the compound containing acarboxyl group produced by the hydrolysis reaction is then optionallysubjected to a salt-forming reaction to give the correspondingcarboxylic acid salt. The salt-forming reaction is known per se, and iscarried out by a neutralization reaction with an inorganic compound,such as potassium hydroxide, sodium hydroxide, and sodium carbonate, oran organic basic compound, such as ammonia, trimethylamine,monoethanolamine, and morpholine, in an amount substantially equal tothat of the carboxylic acid according to a conventional method.

In the case where an ethynylene group of X in the formula [I] is reducedto an ethylene group or a vinylene group or X is reduced to an ethylenegroup, and in the

case where a C₃ -C₈ alkynyl group of R⁵ in the formula [I] is reduced toa C₃ -C₈ alkyl group or a C₃ -C₈ alkenyl group of R⁵ is reduced to a C₃-C₈ alkyl group, it is preferable to adopt a catalytic reduction methodusing a hydrogenation catalyst such as a palladium type catalyst, aplatinum catalyst, a rhodium catalyst and a ruthenium type catalyst.

The palladium type catalysts include palladium-activated carbon,palladium-calcium carbonate and palladium-barium sulfate. Of these,palladium-activated carbon is preferable.

As the platinum catalyst, there may be used platinum oxides and platinumblack.

The rhodium catalyst include chlorotris (triphenylphosphine) rhodium(I).

There is given one example of the reaction conditions hereunder. Whenpalladium-activated carbon is used as a hydrogenation catalyst, ethylacetate, ethanol or methanol is used as the reaction solvent. A severalhours to several days reaction time is usually satisfactory at roomtemperature under atmospheric pressure.

The present invention has the noticeable feature that when the catalyticreduction is effected in deuterium or tritium, the 7-thiaprostaglandinsE₁ of the formula [I] labelled with deuterium or tritium are obtained.Such deuterium- or tritium-labelled compounds are useful for thedetermination of the corresponding 7-thiaprostaglandins E₁ useful as amedicine or for the study on the in vivo behaviour of these compounds.The process of the present invention is also useful from this point.

In the case where an ethynylene group of X in the formula [I] is reducedto a vinylene group, or a C₃ -C₈ alkyl group of X is reduced to a C₃ -C₈alkenyl group, a lindlar catalyst or a palladium-barium sulfate poisonedwith quinoline is preferably used.

In the novel 7-thiaprostaglandins E₁ represented by the formula [I]which are prepared by the above-mentioned process, the7-thiaprostaglandins E₁ which are compounds of the formula [I'] in whichR² and R³ are hydrogen atoms and their enantiomers or mixtures thereofin any ratio: ##STR11## wherein R¹, R⁴, R⁵, X, n and the expression arethe same as defined above, have interesting physiological activities andcan be used for the prevention and/or treatment of various diseases suchas digestive organ diseases, e.g., a duodenal ulcer and a gastric ulcer,liver diseases, e.g., hepatitis, toxipathic hepatitis, fatty liver,hepatic coma, hypertrophy of the liver, and hepatocirrhosis, pancreas,e.g., pancreatitis, arinary diseases, e.g., diabetes kidney diseases,acute kidney insufficiency, cystitis, and urethritis; respiratorydiseases, e.g., pneumatic and bronchitis; incretion diseases; immunitydiseases, toxicoses, e.g., alcohol poisoning and carbon tetrachloridepoisoning and low blood pressure.

The 7-thiaprostaglandins E₁ of the present invention are especiallyuseful for the treatment and prevention of digestive organ diseases suchas a duodenal ulcer and a gastric ulcer.

The present invention will be explained in more detail by the followingexamples which by no means limit the present invention.

EXAMPLE 1 Synthesis of(16RS)-15-deoxy-11-t-butyldimethylsilyl-16-t-butyldimethylsilyloxy-7-thiaprostaglandinE₁ methyl ester

d1-(E)-4-t-butyldimethylsilyloxy-1-iodo-1-octene (1.77 g, 4.8 mmol) wasdissolved in ether (10 ml) and cooled to -78° C. Thereafter,t-butyllithium (2.0M, 4.8 ml, 9.6 mmol) was added to the solution andthe mixture was stirred at a temperature of -78° C. for 2 hours.Phenylthiocopper (I) (828 mg, 4.8 mmol) and a solution ofdexamethylphosphortriamide (1.56 g, 9.6 mmol) in ether (4 ml) were addedto the reaction mixture and the resultant mixture was stirred at atemperature of -78° C. for 1 hour. Then, a solution of(4R)-4-t-butyldimethylsilyloxy-2-(5-methoxycarbonylpentylthio)-2-cyclopentenone(1.49 g, 4.0 mmol) in tetrahydrofuran (70 ml) was added to the reactionmixture and the resultant mixture was stirred at a temperature of -78°C. for 15 minutes and at a temperature of -40° C. for 45 minutes.

An acetate buffer solution was added to the reaction mixture. Theorganic layer was extracted with hexane (150 ml×3), and the separatedorganic layer was washed with an aqueous sodium chloride, dried overanhydrous magnesium sulfate, filtered and concentrated to obtain 2.44 gof a crude product. The crude product was subjected to silica gel columnchromatography (hexane : ethyl acetate=4 : 1) to obtain the desired(16RS)-15-deoxy-11-t-butyldimethylsilyl-16-t-butyldimethylsilyloxy-7-thiaprostaglandinE₁ methyl ester (2.23 g, 3.63 mmol, 91%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.06 (12H, s), 0.87 (21H),1.1˜1.9 (12H, m), 1.9˜3.1 (10H, m), 3.61 (3H, s), 3.27˜4.4 (2H, m),5.1˜5.7 (2H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 1740, 1195, 1165, 960,830, 770

Mass Spectrometric Analysis (FD-MS); 614 (M⁺)

EXAMPLE 2 Synthesis of (16RS)-15-deoxy-7-thiaprostaglandin E₁ methylester

The(16RS)-15-deoxy-11-t-butyldimethylsilyl-16-t-butyldimethylsilyloxy-7-thiaprostaglandinE₁ methyl ester (1.20 g, 1.95 mmol) was dissolved in acetonitrile (60ml). The resultant solution was added with 47% hydrofluoric acid (1 ml)and stirred at room temperature for 1 hour. The reaction mixture wasneutralized with an aqueous solution of sodium hydrogen carbonate, andextracted with ethyl acetate (200 ml×3). The separated organic layer waswashed with an aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated to obtain 750 mg of a crude product.The crude product was subjected to silica gel column chromatography(hexane : ethyl acetate=1:3) to obtain the desired(16RS)-15-deoxy-7-thiaprostaglandin E₁ methyl ester (680 mg, 176 mmol,90%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.87 (3H, t), 1.1˜1.7 (12H,m), 2.0˜3.1 (2H, m), 3.61 (3H, s), 3.2˜4.5 (2H, m), 5.4˜5.75 (2H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3400, 1740, 1260, 845,730

Mass Spectrometric Analysis (FD-MS): 386 (M⁺)

High Resolution Mass Spectrometric Analysis; Analytical value: 386, 2102Calcined value: 386, 2124 (C₂₀ H₃₄ O₅ S)

EXAMPLE 3 Synthesis of(16RS)-15-deoxy-11-t-butyl-dimethylsilyl-16-trimethylsilyloxy-16-methyl-7-thiaprostaglandinE₁ methyl ester

Dry ether (5 ml) was cooled to -78° C. and was added with at-butyllithium solution (1.9M, 2.3 ml, 4.4 mmol). A solution ofd1-(E)-4-trimethylsilyloxy-4-methyl-1-iodo-1-octene (749 mg, 2.2 mmol)in dry ether (5 ml), which had been cooled to -78° C., was added to theabove-prepared solution while stirring at a temperature of -78° C. andthe resultant mixture was stirred at a temperature of -78° C. for 1.5hours Hexamethylphosphortriamide (1.0 ml, 5.5 mmol) was added tophenylthiocopper (I) (380 mg, 2.2 mmol) and the mixture was stirred for1 hour. Dry tetrahydrofuran (5 ml) was added to the mixture and theresultant mixture was cooled to -78° C. This mixture was added theabove-prepared reaction mixture. After the resultant mixture wa stirredat a temperature of -78° C. for 15 minutes, a solution of(4R)-4-t-butyldimethylsilyloxy-2-(5-methoxycarbonylpentylthio)-2-cyclopentenone(745 mg, 2.0 mmol) in dry tetrahydrofuran (20 ml) was added theretoafter cooling to -78° C. The resultant mixture was stirred at atemperature of -78° C. for 30 minutes and at a temperature of -40° C.for 1 hour. The reaction mixture was poured in an acetate buffersolution (70 ml) having a pH of 4, followed by stirring for 15 minutes.The resultant solution was added with hexane (50 ml) and filteredthrough Celite and the filtrate was separated. The aqueous layer wasextracted two times with hexane and the extracted organic layers werecombined with the organic layer. The mixture was washed once with anaqueous saturated ammonium chloride solution containing aqueous ammonia,twice with an aqueous saturated ammonium chloride solution and twicewith an aqueous saturated sodium chloride solution. The washed mixturewas dried over anhydrous magnesium sulfate, filtered, concentrated andsubjected to silica gel column chromatography (cyclohexane : ethylacetate=20:1) to obtain(16RS)-15-deoxy-11-t-butyldimethylsilyl-16-trimethylsilyloxy-16-methyl-7-thiaprostaglandinE₁ methyl ester (904 mg, 1.54 mmol, 77%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.0˜0.2 (15H, m), 0.88 (9H,s), 0.7˜1.0 (3H, m), 1.18 (3H, s), 1.1˜2.0 (12H, m), 2.0˜3.1(10H, m),3.61 (3H, s), 3.8˜4.2 (1H, m), 5.2˜6.0 (2H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 1743, 1248, 835, 773

Mass Spectrometric Analysis (FD-MS); 586 (M⁺)

EXAMPLE 4

Synthesis or (16RS)-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁methyl ester

The(16RS)-15-deoxy-11-t-butyldimethylsilyl-16-trimethylsilyloxy-16-methyl-7-thiaprostaglandinE₁ methyl ester (800 mg, 1.36 mmol) obtained in Example 3 was dissolvedin acetonitrile (10 ml). To this solution, pyridine (1 ml) and hydrogenfluoride-pyridine (2 ml) were added, and the mixture was stirred at roomtemperature for 1.5 hours. The reaction mixture was poured on an aqueoussaturated sodium hydrogen carbonate solution (70 ml) and the resultantmixture was extracted with ethyl acetate. The aqueous layer wasextracted twice with ethyl acetate and the extracted organic layers werecombined. The extracted layer was washed with 1N hydrochloric acid, anaqueous solution saturated with sodium hydrogen carbonate and an aqueoussaturated sodium chloride solution in that order, and was dried withanhydrous sodium carbonate. After filtration and concentration, theresultant product was subjected to silica gel column chromatography(cyclohexane:ethylacetate:methanol=2 : 2 : 0.04) to obtain the desired(16RS)-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁ methyl ester(480 mg, 1.20 mmol, 88%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.88 (3H, t), 1.14 (3H, s),1.0˜1.9 (12H, m), 2.0˜3.4 (11H, m), 3.61 (3H, s), 3.6˜4.5 (2H, m),5.2˜6.0 (2H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3420, 1738

Mass Spectrometric Analysis (FD-MS); 400 (M⁺)

EXAMPLE 5 Synthesis of(16RS)-15-deoxy-16-hydroxy-16-methyl-7-thiaprostanglandin E₁

The (16RS)-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁ methylester (400 mg, 1.0 mmol) obtained in Example 4 was dissolved in acetone(4 ml). To this solution, a phosphoric acid buffer (40 ml) having a pHof 8 was added, followed by the addition of swine liver esterase(produced by Sigma Co., No. E-3128, pH 8, 0.4 ml). The resultant mixturewas stirred at room temperature for 24 hours. After the completion ofthe reaction, the reaction mixture was acidified to a pH of 4 with 0.1Nhydrochloric acid and the aqueous layer was saturated with ammoniumsulfate. Thereafter, the aqueous layer was extracted with ethyl acetateand the extract was washed with an aqueous sodium chloride solution.After the washed extract was dried over magnesium sulfate, it wasconcentrated in vacuo to obtain a crude product. The crude product wassubjected to silica gel column chromatography (hexane:ethyl acetate=1:4,0.1% acetic acid) to purify it, thereby isolating(16RS)-15-deoxy-16-hydroxy-16-methyl-7 -thiaprostaglandin E₁ (340 mg,0.88 mmol, 88%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.86 (3H, t), 1.13 (3H, s),1.0˜1.9 (12H, m), 2.0˜3.4 (11H, m), 3.6˜4.5 (2H, m), 5.2˜6.0 (2H, m),6.23 (1H, bs)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3400, 1740, 1710

EXAMPLE 6 Synthesis of(16RS)-15-deoxy-11-t-butyldimethylsilyl-16-trimethylsilyloxy-16-vinyl-7-thiaprostaglandinE₁ methyl ester

d1-(E)-4-trimethylsilyloxy-4-vinyl-1-iodo-1-octene (1.79 g, 5.25 mmol),t-butyllithium (1.9M, 5.5 ml, 10.5 mmol), phenylthiocopper (906 mg, 5.25mmol), and(4R)-4-t-butyldimethylsilyloxy-2-(5-methoxycarbonylpentylthio)-2-cyclopentenone(1.86 g, 5.0 mmol) were reacted according to the same procedures asthose described in Example 1 in the same manner as in Example 1. Thesame post-treatment and column separation as in Example were effected toobtain the desired(16RS)-15-deoxy-11-t-butyldimethylsilyl-16-trimethylsilyloxy-16-vinyl-7-thiaprostaglandinE₁ methyl ester (2.72 g, 4.65 mmol, 93%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.04 (6H, s), 0.09 (9H, s),0.85 (12H), 1.1˜1.9 (12H, m), 1.9˜3.1 (10H, m), 3.63 (3H, s), 3.8˜4.2(1H, m), 4.8˜5.6 (5H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3080, 1740, 1250, 835,775

Mass Spectrometric Analysis (FD-MS), 586 (M⁺)

EXAMPLE 7 Synthesis of(16RS)-15-deoxy-16-hydroxy-16-vinyl-7-thiaprostaglandin E₁ methyl ester

The(16RS)-15-deoxy-11-t-butyldimethylsilyl-16-trimethylsilyloxy-16-vinyl-7-thiaprostaglandinE₁ methyl ester (1.76 g, 3.0 mmol) obtained in Example 6 was reacted inthe same manner as in Example 4. The same post-treatment and columnseparation as in Example 4 were effected to obtain(16RS)-15-deoxy-16-hydroxy-16-vinyl-7-thiaprostaglandin E₁ methyl ester(1.04 g, 2.61 mmol, 87%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.87 (3H, t), 1.1˜1.7 (12H,m), 2.0˜3.1 (12H, m), 3.60 (3H, s), 3.8˜4.4 (1H, m), 4.8˜5.7 (5H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3400, 3080, 1740,1160, 1080, 970, 730

Mass Spectrometric Analysis (FD-MS); 400 (M⁺)

EXAMPLE 8 Synthesis of(16RS)-15-deoxy-2,3-dehydro-11-t-butyldimethylsilyl-16-t-butyldimethylsilyloxy-7-thiaprostaglandinE₁ methyl ester

d1-(E)-4-t-butyldimethylsilyloxy-1-iodo-1-octene (1.77 g, 4.8 mmol),t-butyllithium (2.0M, 4.8 ml, 9.6 mmol), phenylthiocopper (828 mg, 4.8mmol), and(4R)-4-t-butyldimethylsilyloxy-2-(5-methoxycarbonyl-4(E)-pentenylthio)-2-cyclopentenone(1.48 g, 4.0 mmol) were reacted according to the same procedures asthose described in Example 1 in the same manner as in Example 1. Thesame post-treatment and column separation as in Example 1 were effectedto obtain the desired(16RS)-15-deoxy-2,3-dehydro-11-t-butyldimethylsilyl-16-t-butyldimethylsilyloxy-7-thiaprostaglandinE₁ methyl ester (2.18 g, 3.56 mmol, 89%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.03 (12H, s), 0.85 (21H),0.8˜2.0 (8H, m), 2.0˜3.1 (10H, m), 3.65 (3H, s), 3.3˜4.4 (2H, m),5.1˜5.7 (2H, m), 5.80 (1H, d, J=16 Hz), 6.85 (1H, dt, J=16 and 6 Hz).Infrared Absorption Spectrum (liquid film, cm⁻¹); 1730, 1660, 1260,1110, 840, 780

Mass Spectrometric Analysis (FD-MS); 612 (M⁺)

EXAMPLE 9 Synthesis of(16RS)-15-deoxy-2,3-dehydro-16-hydroxy-7-thiaprostaglandin E₁ methylester

The(16RS)-15-deoxy-2,3-dihydro-11-t-butyldimethylsilll-16-t-butyldimethylsilyloxy-7-thiaprostaglandinE₁ methyl ester (1.84 g, 3.0 mmol) was reacted in the same manner as inExample 4. The same post-treatment and column separation as in Example 4were effected to obtain(16RS)-15-deoxy-2,3-dehydro-16-hydroxy-7-thiaprostaglandin E₁ methylester (956 mg, 2.49 mmol, 83%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.87 (3H), 1.0˜2.8 (20H),3.65 (3H, s), 3.3˜4.4 (2H, m), 5.1˜5.7 (2H, m), 5.82 (1H, d, J=16 Hz),6.87 (1H, dt, J=16 and 6 Hz)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3420, 1740, 1720,1660, 1270, 1080, 975, 730

Mass Spectrometric Analysis (FD-MS); 384 (M⁺)

EXAMPLE 10 Synthesis of(4Z)-(16RS)-11-t-butyldimethylsilyl-4,5-dehydro-15-deoxy-16-methyl-16-trimethylsilyloxy-7-thiaprostaglandinE₁ methyl ester

In the same manner as in Example 1, fromd1-(E)-4-trimethylsilyloxy-1-iodo-1-octene, and(R)-4-t-butyldimethylsilyloxy-2-((Z)-5-methoxycarbonyl-2-pentenylthio)-2-cyclopentenone,(4Z)-(16RS)-11-t-butyldimethylsilyl-4,5-dehydro-15-deoxy-16-methyl-16-trimethylsilyloxy-7-thiaprostaglandinE₁ methyl ester was obtained in a yield of 79%.

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.0˜0.2 (15H, m), 0.87 (9H,s), 0.7˜1.0 (3H, m), 1.18 (3H, s), 1.1˜2.0 (6H, m), 2.0˜3.1 (12H, m),3.61 (3H, s), 1.1˜2.0 (6H, m), 2.0˜3.1 (12H, m), 3.61 (3H, s), 3.8˜4.2(1H, m), 5.2˜6.0 (4H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3080, 1740, 1250, 835,775

Mass Spectrometric Analysis (FD-MS); 584 (M⁺)

EXAMPLE 11 Synthesis of(4Z)-(16RS)-4,5-dehydro-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandinE₁ methyl ester

The(4Z)-(16RS)-11-t-butyldimethylsilyl-4,5-dehydro-15-deoxy-16-methyl-16-trimethylsilyloxy-7--thiaprostaglandinE₁ methyl ester obtained in Example 10 was subjected to exactly the samedeprotection, post-treatment and purification, so as to obtain(4Z)-(16RS)-4,5-dehydro-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁ methyl ester in a yield of 83%.

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.88 (3H, t), 1.14 (3H, S),1.1˜2.0 (6H, m), 2.0˜3.4 (14H, m), 3.61 (3H, s), 3.6˜4.5 (2H, m),5.2˜6.0 (4H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3420, 1740, 1260, 845,730

Mass Spectrometric Analysis (FD-MS); 398 (M⁺)

EXAMPLE 12 Synthesis of(16S)-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁ methyl ester

Exactly the same manner as in Example 3 was repeated except that(1E)-(4S)-4-trimethylsilyloxy-4-methyl-1-iodo-1-octene ([α]²⁴ +1.6°(C=0.62, CHCl₃)) was used in place of thed1-(E)-4-trimethylsilyloxy-4-methyl-1-iodo-1-octene. Thus,(16S)-15-deoxy-11-t-butyldimethylsilyl-16-trimethylsilyloxy-16-methyl-7-thiaprostaglandinE₁ methyl ester (82%) was obtained. The spectral data of this productagreed with those of the product of Example 3.

Then, the above-mentioned product was subjected to exactly the samedeprotection method as in Example 4 to obtain(16S)-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁ methyl ester(91%). The spectral data of this product agreed with those of theproduct of Example 4.

EXAMPLE 13 Synthesis of(16R)-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁ methyl ester

Exactly the same manner as in Example 3 was repeated except that(1E)-(4R)-4-trimethylsilyloxy-4-methyl-1-iodo-1octene ([α]²⁴ -1.6°(C=0.59, CHCl₃)) was used in place of thed1-(E)-4-trimethylsilyloxy-4-methyl-1-iodo-1-octene. Thus,(16R)-15-deoxy-11-t-butyldimethylsilyl-16-trimethylsilyloxy-16-methyl-7-thiaprostaglandinE₁ methyl ester (87%) was obtained. The spectral data of this productagreed with those of the product of Example 3.

Then, the above-mentioned product was subjected to exactly the samedeprotection method as in Example 4 to obtain(16R)-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁ methyl ester(86%). The spectral data of this product agreed with those of theproduct of Example 4.

EXAMPLE 14 Synthesis of11,15-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro-7-thiaprostaglandin E₁methyl ester

(E)-(3S)-t-butyldimethylsilyloxy-1-iodo-1-octene (4.39 g, 11.94 mmol)was dissolved in ether (20 ml) and cooled to -78° C. Then,t-butyllithium (1.9M, 12.9 ml, 23.9 mmol) was added to the solution andthe resultant mixture was stirred at a temperature of -78° C. for 2hours. Phenylthiocopper (2.06 g, 11.94 mmol) and a solution ofhexamethylphosphorustriamide (5.84 g, 35.8 mmol) in ether (20 ml) wereadded to the reaction mixture, and the resultant mixture was stirred ata temperature of -78° C. for 1 hour. Then, a solution ofpentynylthio)-2-cyclopentenone(R)-4-t-butyldimethylsilyloxy-2-(5-methoxycarbonyl-2-cyclopentenone(3.95 g, 10.7 mmol) in tetrahydrofuran (50 ml) was added to the abovemixture, and the resultant mixture was stirred at a temperature of -78°C. for 15 minutes and at a temperature of -40° C. for 30 minutes.

The reaction mixture was added with a 2M acetate buffer solution and wasextracted with hexane (150 ml×3). Each organic layer was washed with anaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered and concentrated so as to obtain 6.8 g of a crudeproduct. The crude product was subjected to silica gel columnchromatography (hexane:ethyl acetate=4:1) to obtain the desired11,15-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro-7-thiaprostaglandin E₁methyl ester (6.83 g, 11.2 mmol, 94%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.06 (12H, s, 0.87 (21H),1.0˜1.8 (8H, m), 2.3˜3.6 (10H, m), 3.67 (3H, s) 3.80˜4.40 (2H, m),5.50˜5.75 (2H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 1745, 1250, 1165,1110, 1075, 965, 885, 835, 805, 775

Mass Spectrometric Analysis (FD-MS); 610 (M⁺)

EXAMPLE 15 Synthesis of 4,4,5,5-dehydro-7-thiaprostaglandin E₁ methylester

The 11,15-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro-7-thiaprostaglandinE₁ methyl ester (1.22 g, 2.0 mmol) obtained in Example 14 was dissolvedin acetonitrile (50 ml). To this solution, pyridine (1.0 ml) and thenhydrogen fluoride-pyridine (2.0 ml) were added, and the resultantmixture was stirred at room temperature for 3 hours. The reactionmixture was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate (150 ml×3). Each of theseparated organic layers was washed with an aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and concentrated toobtain 780 mg of a crude product. The crude product was subjected tosilica gel column chromatography (hexane:ethyl acetate=1:3) to obtainthe desired 4,4,5,5-dehydro-7-thiaprostaglandin E₁ methyl ester (710 mg,1.86 mmol, 93%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.7˜1.0 (3H, m), 1.0˜1.8(8H, m), 2.3˜3.5 (12H, m), 3.67 (3H, s) 3.8˜4.4 (2H, m), 5.6˜5.8 (2H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3400, 1740, 1260, 845,730

Mass Spectrometric Analysis (FD-MS); 382 (M⁺)

EXAMPLE 16 Synthesis of11,15-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro-17(R),20-dimethyl-7-thiaprostaglandinE₁ methyl ester

The same procedures as those described in Example 14 were repeatedexcept that (E)-(3S,5R)-3-t-butyldimethylsilyloxy-5-methyl-1-iodo-1-nonen was used in placeof the (E)-(3S)-t-butyldimethylsilyloxy-1-iodo-1-octene, and1-pentynylcopper was used in place of the phenylthiocopper. Thus,11,15-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro-17(R),20-dimethyl-7-thiaprostaglandin E₁ methyl ester was obtained in a yieldof 89%.

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.06 (12H, s) 0.87 (24H),1.0˜1.8 (9H, m), 2.3˜3.6 (10H, m), 3.67 (3H, s), 3.85˜4.35 (2H, m),5.50˜5.75 (2H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 1745, 1250, 1165,1110, 1075, 965, 885, 835, 805, 775

Mass Spectrometric Analysis (FD-MS); 638 (M⁺), 581 (M-57), 57

EXAMPLE 17 Synthesis of4,4,5,5-dehydro-17(R),20-dimethyl-7-thiaprostaglandin E₁ methyl ester

The 11,15-bis(t-butyldimethylsilyloxy)-4,4,5,5-dehydro-17(R),20-dimethyl-7-thiaprostaglandin E₁ methyl ester obtained in Example 16was subjected to exactly the same deprotection reaction, post-treatmentand purification as those described in Example 2, so as to obtain4,4,5,5-dehydro-17(R),20-dimethyl-7-thiaprostaglandin E₁ methyl ester ina yield of 79%.

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.7˜1.0 (6H, m), 1.0˜1.9(9H, m), 2.3˜3.5 (12H, m), 3.67 (3H, s) 3.8˜4.4 (2H, m), 5.6˜5.8 (2H,m).

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3400, 1740, 1240,1200, 1165, 1075, 1040, 965, 735.

Mass Spectrometric Analysis (FD-MS); 410 (M⁺)

EXAMPLE 18 Synthesis of(4E)-11,15-bis(t-butyldimethylsilyl)-4,5-dehydro-16,17,18,19,20-pentanor-15-cyclohexyl-7-thiaprostaglandinE₁ methyl ester

According to the same manner as in Example 14, from(E)-(3S)-t-butyldimethylsilyloxy-3-cyclohexyl-1-iodo-1- propene and(R)-4-t-butyldimethylsilyloxy-2-((E)-5-methoxycarbonyl-2-pentenylthio)-2-cyclopentenone,(4E)-11,15-bis(t-butyldimethylsilyl)-4,5-dehydro-16,17,18,19,20-pentanol-15-cyclohexyl-7-thiaprostaglandinE₁ methyl ester was obtained in a yield of 87%.

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.06 (12H, s), 0.87 (18H,s), 0.8˜1.9 (11H, m), 1.9˜3.1 (10H, m), 3.7˜4.3 (2H, m), 3.65 (3H, s),5.2˜5.8 (4H, m).

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3080, 1740, 1270,1200, 1080, 975, 885, 835, 805, 775.

Mass Spectrometric Analysis (FD-MS); 624 (M⁺)

EXAMPLE 19 Synthesis of(4E)-4,5-dehydro-16,17,18,19,20-pentanor-15-cyclohexyl-7-thiaprostaglandinE₁ methyl ester

The (4E)-11,15-bis(t-butyldimethylsilyl)-4,5-dehydro-16,17,18,19,20-pentanor-15-cyclohexyl-7-thiaprostaglandin E₁methyl ester obtained in Example 18 was subjected to exactly the samedeprotection, post-treatment and purification as those described inExample 15, so as to obtain(4E)-4,5-dehydro-16,17,18,19,20-pentanor-15-cyclohexyl-7-thiaprostaglandinE₁ methyl ester in a yield of 86%.

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.8˜1.9 (11H, m), 1.9˜3.2(12H, m), 3.7˜4.3 (2H, m), 3.63 (3H, s), 5.2˜5.8 (4H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3420, 3080, 1740,1270, 1200, 1080, 975, 910, 730.

Mass Spectrometric Analysis (FD-MS); 396 (M⁻¹).

EXAMPLE 20 Synthesis of(4Z)-11,15-bis(t-butyldimethylsilyl)-4,5-dehydro-7-thiaprostaglandin E₁methyl ester 7-thiaprostaglandin

The 11,15-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro-7-thiaprostaglandinE₁ methyl ester (610 mg, 1.0 mmol) obtained in Example 14 was dissolvedin ethyl acetate (10 ml). The solution was added with 50 mg of a lindlarcatalyst and was stirred at room temperature for 24 hours. The catalystwas filtered off and the reaction mixture was washed with ethyl acetateand concentrated to obtain a crude product. The crude product wassubjected to silica gel column chromatography (hexane:ethyl acetate=4:1)so as to obtain the desired(4Z)-11,15-bis(t-butyl-dimethylsilyl)-4,5-dehydro-7-thiaprostaglandin E₁methyl ester (428 mg, 0.70 mmol, 70%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.06 (12H, s), 0.87 (3H,s), 1.0˜1.8 (8H, m), 2.3˜3.6 (10H, m), 3.67 (3H, s), 3.8˜4.4 (2H, m),5.2˜5.8 (4H, m).

Absorption Spectrum (liquid film, cm⁻¹); 1745, 1250, 1165, 1110, 1075,965, 885, 835, 805, 775.

Mass Spectrometric Analysis (FD-MS); 612 (M⁺).

EXAMPLE 21 Synthesis of (4Z)-4,5-dehydro-7-thiaprostaglandin E₁ methylester

The (4Z)-11,15-bis(t-butyldimethylsilyl)-4,5-dehydro-7-thiaprostaglandinE₁ methyl ester (306 mg, 0.5 mmol) obtained in Example 20 was subjectedto exactly the same deprotection, post-treatment and purification asthose described in Example 2, so as to obtain(4Z)-4,5-dehydro-7-thiaprostaglandin E₁ methyl ester (177 mg, 0.46 mmol,92%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.88 (3H, t), 1.0˜1.8 (8H,m), 2.2˜3.6 (12H, m), 3.63 (3H, s), 3.8˜4.4 (2H, m), 5.2˜5.8 (4H, m)

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3400, 1740, 1260, 845,730.

Mass Spectrometric Analysis (FD-MS); 384 (M⁺)

EXAMPLE 22 Synthesis of 4,4,5,5-dehydro-7-thiaprostaglandin E₁

The 4,4,5,5-dehydro-7-thiaprostaglandin E₁ methyl ester (191 mg, 0.5mmol) obtained in Example 15 was dissolved in acetone (2 ml). To thissolution, a phosphoric acid buffer solution (20 ml) having a pH of 8 wasadded and then, swine liver esterase (produced by Sigma Co., No. E-3128,pH 8, 0.2 ml) was added. The resultant mixture was stirred at roomtemperature for 24 hours. After the completion of the reaction, thereaction mixture was acidified to a pH of 4 with 0.1N hydrochloric acid.After the aqueous layer was saturated with ammonium sulfate, it wasextracted with ethyl acetate and the extract was washed with an aqueoussodium chloride solution. The organic layer was dried over magnesiumsulfate and concentrated in vacuo to obtain a crude product. The crudeproduct was subjected to silica gel column chromatography (hexane:ethylacetate=1:4, 0.1% acetic acid) to purify it, thereby obtaining4,4,5,5-dehydro-7-thiaprostaglandin E₁ (162 mg, 0.44 mmol, 88%).

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.7˜1.0 (3H, m), 1.0˜1.8(8H, m), 2.3˜3.5 (10H, m), 3.8˜4.4 (2H, m), 5.6˜5.8 (2H, m), 6.30 (3H,bs).

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3400, 1740, 1710.

Mass Spectrometric Spectrum (FD-MS); 368 (M⁺)

EXAMPLE 23 Synthesis of (4Z)-4,5-dehydro-7-thiaprostaglandin E₁

The (4Z)-4,5-dehydro-7-thiaprostaglandin E₁ methyl ester obtained inExample 21 was subjected to exactly the same hydrolysis method as inExample 22, so as to obtain the corresponding(4Z)-4,5-dehydro-7-thiaprostaglandin E₁ .in a yield of 87%.

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.88 (3H, t), 1.0˜1.8 (8H,m), 2.2˜3.6 (10H, m), 3.8˜4.4 (2H, m), 5.2˜5.8 (4H, m), 6.50 (3H, bs).

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3400, 1740, 1710.

Mass Spectrometric Analysis (FD-MS); 370 (M⁺).

EXAMPLE 24 Synthesis of (17R),20-dimethyl-7-thiaprostaglandin E₁-4,4,5,5-d₄ methyl ester

11,15-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro-(17R),20-dimethyl-7-thiaprostaglandin E₁ methyl ester, which was used as thestarting material, was catalytically reduced with deuterium in thepresence of a hydrogenation catalyst consisting of 10%palladium-activated carbon. The resultant product was subjected todeprotection to obtain (17R), 20-dimethyl-7-thiaprostaglandin E₁-4,4,5,5-d₄ methyl ester.

EXAMPLE 25 Synthesis of (17R),20-dimethyl-7-thiaprostaglandin E₁-4,4,5,5-t₄ methyl ester

11,15-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro-(17R),20-dimethyl-7-thiaprostaglandinE₁ methyl ester, which was used as the starting material, wascatalytically reduced with tritium in the presence of a hydrogenationcatalyst consisting of 10% palladium-activated carbon. Thus,(17R),20-dimethyl-7-thiaprostaglandin E₁ -4,4,5,5-t₄ methyl ester wasobtained.

EXAMPLE 26 Synthesis of19,20-dehydro-17,20-dimethyl-11,15-bis(t-butyl-dimethylsilyl)-7-thiaprostaglandinE₁ methyl ester

(i) A solution of 2.2M t-butyllithium in pentane (1.6 ml, 3.48 mmol) wasadded to a solution of 686 mg of (1E, 3S,5R)-1-iodo-5-methyl-1,7-nonadiene-3-ol t-butyldimethylsilylether inether (5 ml) at a temperature of -78° C. The resultant solution wasstirred for 2 hours. Hexamethylphosphorustriamide (567 mg, 3.48 mmol)was added to a suspension of phenylthiocopper (I) (300 mg, 1.74 mmol) inether (2 ml) and the mixture was stirred at room temperature until auniform solution was obtained. Then, this uniform solution was added tothe above-prepared solution, and the mixture was stirred at atemperature of -78° C. for 1 hour. To this solution, a solution of4(R)-t-butyldimethylsilylexy-2-(5-methoxycarbonylpentylthio)-2-cyclopentenone(647 mg, 1.74 mmol) in tetrahydrofuran (20 ml) was added, and themixture was reacted at a temperature of -78° C. for 15 minutes and at atemperature of -40° C. for 1 hour. After the completion of the reaction,an aqueous ammonium chloride solution containing ammonia was added tothe reaction mixture. The aqueous layer was extracted with ether (100ml×3) and the extract was washed with an aqueous ammonium chloridesolution, dried (MgSO₄) and concentrated to obtain a crude product. Thecrude product was subjected to column chromatography to purify it. Thus,990 mg (yield 89%) of(17R)-19,20-dehydro-17,20-dimethyl-11,15-bis(t-butyldimethylsilyl)-7-thiaprostaglandinE₁ methyl ester was obtained in the 5% ethyl acetate-n-hexane eluatefraction. (The configuration of the Δ¹⁹ -double bond of this productcontained 80 to 90% of Z-form.

Nuclear Magnetic Resonance (CDCl₃, S(ppm)); 0.88 (21H, bs), 3.65 (3H,S), 3.8˜4.4 (2H, m), 5.2˜5.7 (4H, m).

Infrared Absorption Spectrum (liquid film, cm⁻¹); 1740, 1252, 1110, 965,882, 835, 775.

Mass Spectrometric Analysis (EI, m/e), 583 (M-tBu), 441, 381, 347, (ii)Similarly, from (1E, 3S,5R)-1-iodo-5-methyl-1,7-nonadiene-3-ol-t-butyldimethyl ether,(17S)-19,20-dehydro-17,20-dimethyl-11,15-bis(t-butyldimethylsilyl)-7-thiaprostaglandinE₁ methyl ester was obtained.

Nuclear Magnetic Resonance (CDCl₃, S(ppm)); 0.88 (21H, bs), 3.66 (3H,S), 3.8˜4.4 (2H, m), 5.2618 5.7 (4H, m)

In Frared Absorption Spectrum (liquid film, cm⁻¹); 1740, 1252, 1110,965, 882, 835, 775.

Mass Spetrometric Analysis (EI, m/e); 583 (M-tBu), 441.

EXAMPLE 27 Synthesis of 19,20-dehydro-17,20-dimethyl-7-thiaprostaglandinE₁ methyl ester

(i) 640 mg of the(17R)-19,20-dehydro-17,20-dimethyl-11,15-bis(t-butyldimethylsilyl)-7-thiaprostaglandinE₁ methyl ester obtained in Example 26 was dissolved in acetonitrile (20ml). To this solution, 0.9 ml of pyridine and then 17 ml of pyridiniumpoly(hydrogen fluoride) were added. The resultant mixture was stirred atroom temperature for 2 hours. The reaction mixture was neutralized withan aqueous solution of sodium hydrogen carbonate and extracted withethyl acetate. The organic layer was washed with a saturated KHSO₄solution, a NaHCO₃ solution and then an aqueous sodium chloridesolution. After drying with MgSO₄, the solvent was distilled away andthe resultant crude product was subjected to silica gel chromatographyto purify it. Thus, 363 mg (yield 88%) of(17R)-19,20-dehydro-17,20-dimethyl-7-thiaprostaglandin E₁ methyl esterwas obtained in the 70 to 80% ethyl acetate-n-hexane eluate fraction.

Nuclear Magnetic Resonance (CDCL₃, δ (ppm)): 0.90 (3H, d, J=5 Hz), 3.60(3H, s), 3.5˜4.4 (4H, br), 5.2˜5.8 (4H, m).

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3425, 1735, 1438,1200, 1172, 1080, 965.

Mass Spectrometric Analysis (EI, m/e); 394 (M-H20), 376 (M-2H₂ O)

(ii) Similarly, from the(17S)-19,20-dehydro-17,20-dimethyl-11,15-bis(t-butyldimethylsilyl)-7-thiaprostaglandinE₁ methyl ester obtained in Example 26,(17S)-19,20-dehydro-17,20-dimethyl-7-thiaprostaglandin E₁ methyl esterwas obtained.

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.90 (3H, d, J=5 Hz), 33.62(3H, s), 3.5˜4.4 (4H, br), 5.2˜5.2 (4H, m).

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3420, 1738, 1438,1200, 1170, 1080, 965.

Mass Spectrometric Analysis (EI, m/e); 394 (M-H₂ O), 376 (M-2H₂ O).

EXAMPLE 28 Synthesis of(16RS)-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁ geranylester

100 mg (0.25 mmol) of(16RS)-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁ wasdissolved in dry methylene chloride (1.2 ml). To this solution, 124 μl(0.72 mmol) of geraniol was added. To this mixture, 9 mg (0.072 mmol) of4- dimethylaminopyridine and then 74 mg (0.36 mmol) ofdicyclohexylcarbodiimide were added under ice cooling, and the mixturewas stirred for 30 minutes and then at room temperature for 1 hour.Ethyl acetate (20 ml) was added to the mixture and the resultant mixturewas Celite filtered. The filtrate was mixed with water and the mixturewas shaken in a separating funnel. The aqueous layer was again extractedwith ethyl acetate (20 ml), after which the combined organic layer waswashed with an aqueous potassium hydrogen sulfate solution, an aqueoussodium hydrogen carbonate solution, and an aqueous solution saturatedwith sodium chloride, and then dried over magnesium sulfate, after whichthe solvent was distilled away. The resultant residue was subjected tosilica gel chromatography to effect separation and purification. Thus,70 mg (yield 52%) of (16RS)-15-deoxy-16-hydroxy-16-methyl-7-thiaprostaglandin E₁ geranyl ester was obtainedin the hexane-ethyl acetate (1:1) eluate fraction.

Nuclear Magnetic Resonance (CDCl₃, δ (ppm)); 0.88 (3H, t), 1.14 (3H, s),1.57 (3H, s), 1.67 (6H, s), 3.9˜4.3 (1H, br), 4.52 (2H, d, J=7 Hz),4.8˜5.4 (2H, br), 5.61 (2H, m).

Infrared Absorption Spectrum (liquid film, cm⁻¹); 3400, 2960, 2940,2860, 1740, 1450, 1160, 965.

EXAMPLE 29 (i) Determination of Antiulcerative Effect

The inhibiting effect on ulcer formation induced by indomethacin wasexamined by using rats. Wister male rats (7 weeks old and body weight of220 g) were abstained from food for 24 hours except giving water andthen subjected to experiments.

The sample compounds to be tested were dissolved in a phosphoric acidbuffer (pH 7.4) containing 0.9% NaCl and the solution was orallyadministered to the rats. 30 minutes after the administration,indomethacin was orally administered to the rats at a dose of 20 mg/kg.5 hours after the administration of the indomethacin, the rats werekilled and the ulcer formation in the stomach was examined bydetermining the length of the ulcer formation portion under astereomicroscope. From this measurement, the inhibition of ulcerformation by the sample compounds were calculated to determine the EDvalues. The results are shown in Table 1.

(ii) In vitro Blood Platelet Aggregation Inhibition Effect

The in vitro blood platelet aggregation inhibition effect of the samplecompounds to be tested was examined by using rabbits. That is, blood wascollected from the ear vein of native Japanese white male domesticrabbits weighing 2.5 to 3.5 kg. The collected blood was 9 parts byvolume per 1 part by volume of a 3.8% sodium citrate solution. The bloodwas centrifuged at 1000 r.p.m. for 10 minutes. The upper layer portionwas separated as PRP (rich in platelet blood plasma). The lower layerportion was further centrifuged at 2800 r.p.m. for 10 minutes to divideit into two layers. The upper layer portion was separated as PPP (poorin platelet blood plasma). The number of the platelet was diluted withPPP to 6 to 7×10³ /μl. After the adjustment, 25 μl of the samplecompound was added to 250 μl of PRP, which was preincubated at atemperature of 37° C. for 2 minutes. Thereafter, 10 μM of ADP (final)was added to the preincubated PRP to record the variation of thetransmittance by means of aggregometer. The sample compounds weredissolved in ethanol to provide 10 mg/ml.

When the activity of the sample compounds was determined, the ethanolsolution was diluted with a phosphoric acid buffer (PH 7.4). The ethanolsolution diluted with the buffer was left to stand at a temperature of0° C. for 4 hours, after which the activity of the sample compounds wasdetermined in the same manner.

The platelet aggregation inhibition was calculated by the followingformula:

    Inhibition (%)≦(1-T.sub.o /T)×100

T_(o) : the transmittance of the system to which the phosphoric acidbuffer is added

T: the transmittance of the system to which the sample compounds areadded

The lowest concentration of the sample compounds at which the inhibitionis 50% was represented as an IC₅₀ value. The results are shown in Table1.

                                      TABLE 1                                     __________________________________________________________________________                                      Anti-platelet                                                       Antiulcerative effect                                                                   aggregation effect                          Compound                ED.sub.50 (μg/kg)P.O                                                                 IC.sub.50 (μg/ml)                        __________________________________________________________________________    Compound of this invention                                                     ##STR12##              10          17                                        Comparative compound                                                           ##STR13##              300       >100                                         ##STR14##              35        0.004                                       __________________________________________________________________________

As is apparent from Table 1, the compounds of the present invention arethose having especially strong antiulcerative effect.

EXAMPLE 30 Determination of Effect against Ethanol Ulcer

SD type male rats (7 weeks old and body weight of 220 g) were abstainedfrom food for 24 hours except giving water and then subjected toexperiments.

The sample compound to be tested was dissolved in a phosphoric acidbuffer (pH 7.4) containing 0.9% NaCl and the solution was orallyadministered to the rats. 30 minutes after the administration, 75%ethanol was orally administered to the rats at a dose of 1 ml/kg. Onehour after the administration of the ethanol, the rats were killed andthe ulcer formation in the stomach was examined by determining thelength of the ulcer formation portion under a stereomicroscope. Fromthis measurement, the inhibition of ulcer formation by the samplecompound was calculated to determine the ED₅₀ value. The result is shownin Table 2.

                  TABLE 2                                                         ______________________________________                                                            Antiulcerative effect                                     Compound            ED.sub.50 (μg/kg)P.O                                   ______________________________________                                        Compound of this invention                                                     ##STR15##          18                                                        ______________________________________                                    

CAPABILITY OF EXPLOITATION IN INDUSTRY

The 7-thiaprostaglandins E₁ of the present invention have interestingphysiological activities and can be used for the prevention and/ortreatment of various diseases such as digestive organ diseases, e.g., aduodenal ulcer and a gastric ulcer; liver diseases, e.g., hepatitis,toxipathic hepatitis, hepatic coma, hepertrophy of the liver, andhepatocirrhosis; pancreas, e.g., pancreatitis; arinary diseases, e.g.,diabetos kidney diseases, acute kidney insufficiency, cystitis, andurethritis; respiratory diseases, e.g., pneumonia and bronchitis;incretion diseases; immunity diseases; toxicosis, e.g., alcoholpoisoning and carbon tetrachloride poisoning and low blood pressure.

The 7-thiaprostaglandins E₁ of the present invention are especiallyuseful for the treatment and prevention of digestive organ diseases suchas a duodenal ulcer and a gastric ulcer.

We claim:
 1. 7 -thiaprostaglandins E₁ which are compounds represented bythe following formula (I) or their enantiomers or mixtures thereof inany ratio: ##STR16## wherein R¹ represents a hydrogen atom, a C₁ -C₁₀alkyl group, a C₂ -C₂₀ alkenyl group, a substituted or unsubstitutedphenyl group, a substituted or unsubstituted C₃ -C₁₀ cycloalkyl group, asubstituted or unsubstituted phenyl (C₁ -C₂) alkyl group, or oneequivalent cation R² and R³, which are the same or different, representa hydrogen atom, a tri(C₁ -C₇) hydrocarbon silyl group, or a groupforming an acetal linkage together with an oxygen atom of a hydroxylgroup; R⁴ represents a hydrogen atom, a methyl group or a vinyl group;R⁵ represents a linear or branched C₃ -C₈ alkyl group, a linear orbranched C₃ -C₈ alkenyl group, a linear or branched C₃₆ l-C₈ alkynylgroup, a substituted or unsubstituted phenyl group, a substituted orunsubstituted C₃ -C₁₀ cycloalkyl group, or a linear or branched C₁ -C₅alkyl group substituted with a C₁ -C₆ alkoxy group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted phenoxy groupor a substituted or unsubstituted C₃ -C₁₀ cycloalkyl group; x representsan ethylene group, a vinylene group or an ethynylene group; n represents0; the expression represents an ethylene group or a vinylene group;provided that, when x is an ethylene group, R⁵ is a linear or branchedC₃ -C₈ alkenyl group; wherein the substituent of the each substitutedgroup mentioned above is a halogen atom, a hydroxy group, a C₂ -C₇acyloxy group, a C₁ -C₄ alkyl group which may be substituted with ahalogen atom, a C₁ -C₄ alkoxy group which may be substituted with ahalogen atom, a nitrile group, a carboxyl group of a (C₁ -C₆)alkoxycarbonyl group.
 2. The 7-thiaprostaglandins E₁ according to claim1 wherein R¹ is a hydrogen atom, a C₁ -C₁₀ alkyl group, a C₂ -C₂₀alkenyl group or one equivalent cation.
 3. The 7-thiaprostaglandins E₁according to claim 1 wherein R⁵ is a butyl group, a pentyl group, a1-methyl-1-butyl group, a 2-methyl-1-butyl group, a cyclopentyl group, acyclohexyl group or a phenyl group.